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Quantumbiology: DNA Replication and Bio-molecular Recognition

Final Activity Report Summary - DNA REPLICATION (Quantumbiology: DNA Replication and Biomolecular Recognition)

By means of the Marie Curie Fellowship, the fellow has taken into account the objective of unravelling the mechanism of the highly accurate, enzyme-assisted DNA replication process and, in particular, understanding the role of hydrogen bonding, steric factors and solvation effects in this multistep process, these are the research topics analysed:

- Effect of aqueous solution on a complete series of Watson-Crick and mismatched base pairs. The effect of solvation on hydrogen bonding has been analysed in a series of base pairs. Geometrically, it has been found how solvation causes an elongation of the hydrogen bonds, and thermodynamically, it is observed the weakening of this interaction.

- Effect of solvation and stacking on a series of pi-stacked Watson-Crick base pair dimers. We have taken into study all possible p-stacked Watson-Crick base pair dimers and analysed the thermochemistry corresponding to the formation of a Watson-Crick base pair with the presence of another pi-stacked base pair. Therefore, it is a model to get closer to the real DNA replication mechanism. It is found that hydration strongly weakens Watson-Crick hydrogen bonding. In addition, pi-stacking strengthens this interaction, however it does not completely compensates the solvent effect. It is observed how the large difference between A-T and G-C base pairs alone is strongly reduced by the combined action of solvation and pi-stacking. Finally, the pairing of the incoming nucleotide depends on the stacking environment, that is, best bonding is achieved if primer strand ends on purine. As a whole, this study incorporates a simple model that is intended to represent a step forward a better comprehension of the complex DNA replication process.

- The above project has been complemented by means of taking a deeper insight of the selectivity for the formation of a Watson-Crick or a mismatched base pair during the DNA replication. We pretended at uncovering and quantifying the effects on this process of solvation, pi-stacking and hydrogen bonding. In particular, these hydrogen-bonds between two adjacent bases from opposite strands (forming a Watson-Crick base pair), and the pi-pi stacking interactions between two bases within each of the two DNA strands are the two major factors for the structure and stability of DNA. By means of this computational work, it is shown how the selectivity of the primer strand towards the formation of a Waston-Crick base pair with the incoming nucleotide is kept without the presence of the enzyme polymerase. And in addition, it is also proven the importance of the steric model in the DNA replication process.

- Effect of metal cation on a series of guanine-cytosine Watson-Crick base pairs in which purine-C8 or pyrimidine-C6 position carry a substituent X = O-, OH, COO-, or COOH. The purpose is to study the effects on structure and hydrogen-bond strength if a metal cation (Na+, K+) is added to substituted guanine-cytosine base pair. It is found that the effect depends on the final charge created by the metal cation and the substituent X. If it is neutral the effect is very small. When having an anionic species, hydrogen-bond donating is reduced and increases the hydrogen-bond accepting capabilities of a DNA base, and vice versa for a cationic substituent. Therefore, along the series the geometric shape and bond strength of our DNA base pair can be chemically switched between there states, thus yielding a chemically controlled supramolecular switch.

In addition, some projects in collaboration with the group where the fellow carried out the PhD have been done, with the fellow as a supervisor of them. And at the same time a side project has consisted of going deeper into the failure of Atoms in Molecules theory when assigning H-H interaction in biphenyl of phenanthrene systems.